A protein product, such as antibody drug, recombinant protein drug, plasma product, plasma fractionation product or the like may be contaminated with viruses derived from a raw material or caused during a production process. Therefore, it is necessary to inactivate or remove viruses in the course of preparing the protein product.
As the method for inactivating viruses that may be mixed into a protein product a heat treatment, a chemical treatment, or the like have been conducted. However, viruses may not be sufficiently inactivated using only such a treatment alone. Moreover, useful proteins themselves contained in a protein product may be denatured during such a treatment. In view of this situation, as a physical virus removal means that do not cause chemical denaturation separation/removal of viruses using a filter membrane have been carried out.
A membrane formed of a natural material such as cellulose and a virus removal membrane formed of a synthetic polymer material such as polyvinylidene fluoride (PVDF) or polyethersulfone (PES) have been known as a virus removal filter membrane (see Non-patent Documents 1 to 4).
When filtering an intermediate product of a protein product (hereinafter, may be referred to as an “intermediate protein product”) using a virus removal apparatus that is provided with these virus removal membranes, it is ideal that a large amount of proteins can be filtered within a short time, and viruses can be removed by a sufficiently high virus removal performance. However in fact though a cellulose membrane, for example, can filter the intermediate protein product without clogging even at a protein concentration of 20 mg/ml or more, allows the practical pressure to be increased to only about 100 kPa due to low pressure resistance. On the other hand, a synthetic polymer membrane allows the practical pressure to be increased to about 300 kPa without problems due to high pressure resistance thereof, but may clog when the protein concentration is increased to about 20 mg/ml and cannot filter. Therefore, the intermediate protein product has been commonly filtered at a low protein concentration of 10 mg/ml or less (see Patent Document 1).
For these reasons, research of a filtration method carrying out under filtration conditions where an intermediate protein product having a high protein concentration that is increased by purification steps, such as various chromatographies, ultrafiltration and the like is passed through a virus removal apparatus at a high pressure have not been developed, and a virus removal filter used suitably for such a method also have not been developed.
Since an intermediate protein product is an important material for preparing a protein product, it is temporally and economically difficult to determine the filtration method and the operating conditions for the virus removal step in a production scale. Therefore, the inventor strongly recognized that it is very important to previously determine the filtration method for the virus removal step, the protein concentration of the intermediate protein product, and the operating conditions of the inlet pressure of the virus removal filter, and/or the filtration time in a small scale, and apply them to the scale-uped protein product production process.    [Patent Document 1] JP-A-2004-277323    [Non-patent Document 1] Manabe S., Removal of virus through novel membrane filtration method, Dev. Biol. Stand., (1996) 88: 81-90    [Non-patent Document 2] Brandwein H. et al., Membrane filtration for virus removal, Dev Biol (Basel), (2000) 102: 157-63    [Non-patent Document 3] Aranha-Creado et al., Clearance of murine leukaemia virus from monoclonal antibody solution by a hydrophilic PVDF microporous membrane filter, Biologicals, June 1998, 26 (2): 167-72    [Non-patent Document 4] L. Moce-Llivina et al., Comparison of polyvinylidene fluoride and polyether sulfone membranes in filtering viral suspensions, Journal of Virological Methods, April 2003, Vol. 109, Issue 1, pages 99-101